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Open Access 01-12-2023 | Research

High dose isoleucine stabilizes nuclear PTEN to suppress the proliferation of lung cancer

Authors: Haiqing Wang, Sen Chen, Wenhui Kang, Bojiao Ding, Shulan Cui, Li Zhou, Na Zhang, Huiying Luo, Mingjuan Wang, Fan Zhang, Zezhou Zhao, Zihu Guo, Chao Wang, Liang Li, Zhengzhong Wang, Xuetong Chen, Yonghua Wang

Published in: Discover Oncology | Issue 1/2023

Abstract

Purpose

Cancer cells require a supply of amino acids, particularly essential amino acids such as branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine), to meet the increased nutrient demands of malignant tumors. The cell-autonomous and non-autonomous roles of altered BCAA supply have been implicated in cancer progression. The critical proteins involved in BCAA uptake, transport, metabolism, etc. serve as potential therapeutic biomarkers in human cancers. Here, we summarize the potential anti-tumor mechanism of BCAA by exploring the chain reaction triggered by increased BCAA supply in the tumor.

Method

A system-wide strategy was employed to provide a generic solution to establish the links between BCAA and cancer based on comprehensive omics, molecular experimentation, and data analysis.

Results

BCAA over-supplementation (900 mg/kg) significantly inhibited tumor growth and reduced tumor burden, with isoleucine having the most pronounced effect. Surprisingly, isoleucine inhibited tumor growth independently of mTORC1 activation, a classical amino acid sensor. Exploratory transcriptome analysis revealed that Phosphatase and tensin homolog (PTEN) is the critical factor in the anti-tumor effect of isoleucine. By inhibiting PTEN ubiquitination, isoleucine can promote PTEN nuclear import and maintain PTEN nuclear stability. Interestingly, this process was regulated by isoleucine-tRNA ligase, cytoplasmic (IARS), a direct target of isoleucine. We demonstrated the enhanced interaction between IARS and PTEN in the presence of excess isoleucine. At the same time, IARS knockout leads to loss of isoleucine tumor suppressor ability.

Conclusion

Overall, our results provide insights into the regulation of the IARS-PTEN anti-tumor axis by isoleucine and reveal a unique therapeutic approach based on enhancing cellular isoleucine supply.

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Title: High dose isoleucine stabilizes nuclear PTEN to suppress the proliferation of lung cancer
Authors: Haiqing Wang
Sen Chen
Wenhui Kang
Bojiao Ding
Shulan Cui
Li Zhou
Na Zhang
Huiying Luo
Mingjuan Wang
Fan Zhang
Zezhou Zhao
Zihu Guo
Chao Wang
Liang Li
Zhengzhong Wang
Xuetong Chen
Yonghua Wang
Publication date: 01-12-2023
Publisher: Springer US
Published in: Discover Oncology / Issue 1/2023
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-023-00634-1

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